Project Summary Export of mRNAs from the nucleus to the cytoplasm is an essential step in eukaryotic gene expression. As mRNA is synthesized, it is processed and packaged with a myriad of proteins to form ribonulceoprotein particles (mRNPs). Our research focuses on determining the specific changes in mRNP protein composition, referred to as mRNP remodeling, that drive the process of mRNA nuclear export. A major step where mRNPs undergo extensive remodeling is the formation of export-competent mRNPs. This is mediated by the evolutionarily conserved TREX (TRanscription/EXport) complex, which recruits transport- specific proteins onto a nuclear mRNP through the actions of its ATPase subunit Sub2. Our recent discovery of the activation mechanism of Sub2 has primed the way toward defining the cascade of molecular events that lead to export-competent mRNPs. Broadly, my lab at Vanderbilt combines the power of structural biology, biochemistry, genetics, and cell biology to elucidate the nuclear mRNP remodeling process with the focus on two areas. First, we will determine the sequence and mechanism of events that prepare nuclear mRNP for export. This includes characterization of the mechanism of key players in nuclear mRNP remodeling and identification of the molecular links between nuclear mRNP remodeling and pre-mRNA processing steps. Second, we will investigate how mRNA export is altered in response to physiological and pathological conditions. We seek to understand how mRNA export is tuned to regulate specific biological processes and how dysregulation of this pathway contributes to human pathogenesis such as viral infection. Ultimately, the knowledge generated from these studies will provide vital insights into the mRNA export pathway that is both of fundamental cell biological importance and is relevant to human health and disease.